Substituted amides of 3-methyl-4-phenyl-3-butenoic acid, with a high hypolipemizing activity

ABSTRACT

Amides of 3-methyl-4-phenyl-3-butenoic acid of the formula ##STR1## wherein R represents hydrogen, alkyl, hydroxyalkyl or cycloalkyl and R&#39; represents alkyl, hydroxyalkyl or cycloalkyl, or R and R&#39; together represent --CH 2  --CH 2  --O--CH 2  --CH 2  --, which are obtained by reacting the chloride of 3-methyl-4-phenyl-3-butenoic acid and amines of formula ##STR2## wherein R and R&#39; have the above indicated meanings, having a high hypolipemizing activity.

Former works had put in evidence that 3-methyl-4-phenyl-3-butenoic acid (I) and its amide (II) have interesting hypolipemic characteristics (U.S. Pat. No. 3,231,469, Jan. 25, 1966; L.Canonica et al. "Il farmaco" sch.edition, 14, 112, 1959; L.Canonica et al J.Biol.Chem. 243, 1645, 1968) ##STR3##

It is now found, surprisingly, that some substituted amides of formula IIIa-e, and particularly the diethylamide of 3-methyl-4-phenyl-3-butenoic acid (IIId),

    ______________________________________                                          ##STR4##                                                                       R                  R'                                                         ______________________________________                                         IIIa = H           CH.sub.2CH.sub.2 OH                                         IIIb = H                                                                                           ##STR5##                                                   IIIc = CH.sub.2CH.sub.2OH                                                                         CH.sub.2CH.sub.2OH                                          IIId = CH.sub.2CH.sub.3                                                                           CH.sub.2CH.sub.3                                            IIIe = CH.sub.2CH.sub.2OCH.sub.2CH.sub.2                                       ______________________________________                                    

exhibit in numerous pharmacologycal tests a remarkably higher hypolipemizing activity than compounds I and II, and in some pharmocological tests a hypolipemizing activity higher than the ethyl ester of 2-(p-chlorophenoxy)-2-methyl propanoic acid (chlofibrate).

Furthermore products IIIa-e, and particularly diethylamide IIId, have a low toxicity in the test animal.

Products IIIa-e have been prepared by condensation of the chloride of 3-methyl-4-phenyl-3-butenoic acid and ethanolamine, cyclohexylamine, diethanolamine, diethylamine, morpholine.

                  TABLE I                                                          ______________________________________                                         LD 50 per os in the rat.                                                       Compound          mg/kg                                                        ______________________________________                                         IIIa              1375                                                         IIIb              3000                                                         IIIc              1500                                                         IIId              2300                                                         IIIe              1000                                                         ______________________________________                                    

                                      TABLE II                                     __________________________________________________________________________     hypertriglyceridemia from Fructose*                                                                        Significance                                                          Significance                                                                            against animal                                               Triglyceridemia                                                                         against  set treated with                                   Treatment mg/100 ml ±SE                                                                        controls Fructose                                           __________________________________________________________________________     controls  41.7±1.7                                                                             --       --                                                 fructose  62.9±5.5                                                                             p<0.01   --                                                 "    + I  42.8±3.7                                                                             not      p<0.02                                             "    + chlofi                                                                            42.2±5.4                                                                             significant                                                                             p<0.05                                                  brate                                                                     "    + IIIa                                                                              62.9±6.4                                                                             p = 0.01 not significant                                    controls  45.6±4.7                                                                             --       --                                                 fructose  94.0±12.1                                                                            p<0.01   --                                                 "    + I  40.8±4.5                                                                             not significant                                                                         p<0.01                                             "    + chlofi                                                                            48.9±2.4                                                                             "        p<0.01                                                  brate                                                                     "    + IIIb                                                                              59.1±7.5                                                                             "        p<0.05                                             "    + IIIc                                                                              69.6±3.9                                                                             p<0.01   not significant                                    controls  77.1±12.1                                                                            --       --                                                 fructose  155.2±19.2                                                                           p<0.01   --                                                 "    + I  100.8±13.8                                                                           not significant                                                                         p≦0.05                                      "    + chlofi                                                                            62.9±7.2                                                                             "        p<0.01                                                  brate                                                                     "    + IIId                                                                              87.1±13.4                                                                            "        p≦0.02                                      controls  45.3±4.5                                                                             --       --                                                 fructose  87.4±14.4                                                                            p<0.02   --                                                 "    + I  57.6±2.6                                                                             p<0.05   p<0.05                                             "    + chlofi                                                                            59.1±3.6                                                                             p<0.05   not significant                                         brate                                                                     "    + IIIe 61.1±5.1                                                                  p<0.05   "                                                           __________________________________________________________________________       *Animal: Sprague-Dawley male rat, 150 g.; 6 rat sets. Treatment accordin      to E. A. Nikkila et al., Life sci.5,89,1966; substances administered at        the dose of 200 mg/kg day by gastric probing in two daily administrations      for 5 days.                                                              

                                      TABLE III                                    __________________________________________________________________________     hyperlipemia from diet*                                                                                                         Hepatic                                                          Hepatic       triglycerides                           Cholesterolemia                                                                             Triglyceridemia°                                                                    Cholesterol°                                                                          mg/g fresh tissue             Treatment mg/100 ml ± SE                                                                           mg/100 ml ± ES                                                                          mg/g fresh tissue ± SE                                                                    ± SE                       __________________________________________________________________________     controls                                                                              (9)                                                                               40.6±1.1(p<0.001)                                                                        65.1±2.3 (p<0.01)                                                                       2.4±0.04 (p<0.001)                                                                        3.8±0.3(p<0.001)           hyperlipidic                                                                   diet   (9)                                                                               129.9±9.3 --                                                                             117.3±17.7 --                                                                           16.4±0.8 --                                                                               56.4+3.8 --                   idem + I                                                                              (6)                                                                               142.4±7.7(not signif)                                                                    91.5±13.6(not si                                                                        20.2±0.9(not signific.)                                                                   37.7±5.6 (p<0.02)                                 gnificat.)                                              idem + chlo-                                                                   fibrate                                                                               (9)                                                                               138.8±10.7 (" ")                                                                         60.0±4.3 (p<0.01)                                                                       18.5±1 (" ")                                                                              30.3±2.5(p<0.001)          idem + IIIb                                                                           (7)                                                                               135.7±11.6 (" ")                                                                         81.5±7.9(not signi                                                                      22.1±1.1 (" ")                                                                            37.5±3.0(p<0.005)                                 ficative)                                               idem + IIId                                                                           (8)                                                                               124.9±4.6 (" ")                                                                          77.4±7.5 (" ")                                                                          19.4±0.7 (" ")                                                                            25.9±3.8                   __________________________________________________________________________                                                      (p<0.001)                      °In parentheses, significativity towards the set treated only with      diet.                                                                          *Animal: Sprague-Dawley male rat of the initial weight of 120 g (in            parentheses the N. of animals).                                          

Treatment: Hyperlipemia derived from hyperlipidic diet according to Nath N. et al., Nutrition J. 67, 289, 1959; the diet has been administered for 4 weeks. Each drug has been administered at the dose of 200/mg/kg/day per os for 4 weeks.

                                      TABLE V                                      __________________________________________________________________________     hyperlipemia from ethanol*                                                                           triglyceri-   Significance                                                     demia  Significance                                                                          against cholesterole-                                    g. alcohol                                                                             mg/100 ml                                                                             against                                                                               set treated                                                                            mia                                Treatment     drunk per rat                                                                          ± SE                                                                               controls                                                                              with ethanol                                                                           mg/100 ml                          __________________________________________________________________________     controls   (10)                                                                              --       87±14                                                                             --     --      85±6                            ethanol    (8)                                                                               16.1    238±44                                                                             p<0.01 --      90±4                             " + chlofibrate                                                                          (7)                                                                               20      183±29                                                                             --     not signific.                                                                          70±3                            200 mg/kg                                                                       " + IIId 200 mg/                                                              kg         (8)                                                                               14.8    169±20                                                                             --     "       77±3                             " + IIId 300 mg/                                                              kg         (11)                                                                              13.2    117±20                                                                             --     p<0.02  81±3                            __________________________________________________________________________       *Animal Treatment:                                                            Sprague-Dawley male rat of the average weight of 150 g. ethyl alcohol 10%      in water for 1 week (in parenthesis, the N. of animals). The substances        have been administered by gastric intubation at the dose of 200 and 300        mg/kg/day. In experiments of subchronic toxicity, the diethylamide of          3-methyl-4-phenyl-3-butenoic acid (IIId) has been administered per os at       the doses of 150 mg/kg/day and of 300 mg/kg/day for 3 or 6 months: the         product has been found fairly well tolerated.                            

                                      TABLE IV                                     __________________________________________________________________________     hypertriglyceridemia from ethanol*                                                                            Significance against                                       Triglyceridemia                                                                         Significance against                                                                      sets treated with                               Treatment  mg/100 ml ± SE                                                                       controls   ethanol                                         __________________________________________________________________________     controls                                                                              (10)                                                                               74.20±3.70                                                                           --         --                                              ethanol                                                                               (10)                                                                               135.80±13.30                                                                         p<0.001    --                                              idem + I                                                                              (9) 275.11±31.63                                                                         --         p<0.001                                         idem + chlo-                                                                          (10)                                                                               121.50±12.26                                                                         --         not significant                                 fibrate                                                                        idem + IIId                                                                           (9) 90.0±14.83                                                                           --         p<0.05                                          __________________________________________________________________________       *Animal: Sprague-Dawley male rat of the average weight of 150 g.              Treatment: 0.31 ml. ethanol in 4 ml. water twice a day (in parenthesis,        the N. of animals) for 4 days. The substances have been provided by            gastric intubation at the daily dose of 300 mg/kg.                       

EXAMPLE 1 Chloride of 3 methyl-4-phenyl-3-butenoic acid.

3 Kg of crystallized pure 3-methyl-4-phenyl-3-butenoic acid are dissolved into 3 l.benzene, 2,5 l of thionylchloride are added, and the mixture is kept 2 hours at 20° C and then taken slowly to 40° C and then refluxed 2 hours.

When the evolution of hydrochloric acid ceases, the excess thionyl chloride and benzene are evaporated under vacuum.

The residue is taken up twice with 2 liters of benzene and it is dry evaporated.

The chloride of 3-methyl-4-phenyl-3butenoic acid is distilled at 13-14 mm. of residual pressure at 118°-125° C: 307 g. chloride are obtained.

Monoethanolamide of 3-methyl-4-phenyl-3-butenoic acid (IIIa).

194 g of 3-methyl-4-phenyl-3-butenoic acid chloride (1 mole), dissolved into 500 ml benzene, are treated at-10° C with 183 g of monoethanolamine (3 moles). The mixture is stirred at 20° C for 3 hours.

It is washed with water, 5% aqueous NaHCO₃ (to remove the chloride of the acid and the non reacted acid), and again with water to neutrality.

The benzene is evaporated under vacuum and the residue is crystallized three times from benzene.

There is obtained 257 g of monoethanolamide IIIa with m.p. 101°-103° C, carbon 71,20% (calculated 71.04%), hydrogen 7.81% (calculated 7.74%), nitrogen 6.38% (calculated 6.18%); ζ_(max) ^(MeOH) 245-246 mμ (E_(1cm) ^(1%) 714), I.R.nujol bands at 3300, 1650, 1550, 1340, 1310, 1280, 1210, 1180, 1080, 1060, 1040, 920, 870, 860, 850, 740, 730, 700 cm⁻¹.

Monocyclohexylamide of 3-methyl-4-phenyl-3-butenoic acid (IIIb).

95.2 g. of cyclohexylamine (0.96 moles ) dissolved into 350 ml of anhydrous chloroform are treated at -15°/-20° C with 93.5 g. of chloride of 3-methyl-4-phenyl-3-butenoic acid(0,48 moles) dissolved into 125 ml chloroform during 1 hour at -15°/-20° C.

The mixture is stirred 2 hours at room temperature, and is then poured into a liter of iced water.

The chloroform is separated and is washed with 150 ml of aqueous 10% HCl, with 150 ml of aqueous 10% NaHCO₃, with 150 ml of water to neutral reaction. After evaporation from the solvent and crystallization from CHCl₃ -ethyl ether, there is obtained 89 g. of monocyclohexylamide (IIIb) with m.p. 122°-123° C., _(max) ^(MeOH) 206 mμ (E_(1cm) ^(1%) 848) and 245 mμ E_(1cm) ^(1%) 633), carbon 79.33 % (calculted 79.40%), hydrogen 9.01% (calculated 9.33%), nitrogen 5.44% (calculated 5.27%), I.R. nujol bands at 3250, 3090, 1660, 1630, 1570, 1350, 1280, 1260, 1250, 1220, 1170, 1100, 1080, 1020, 990, 920, 890, 770, 750, 730, 700 cm⁻¹.

Diethanolamide of 3-methyl-4-phenyl-3-butenoic acid (IIIc).

100 g. of diethanolamine dissolved into 350 ml of CHCl₃ are treated at -15°/-20° C within 1 hour with 93 g. of chloride of 3-methyl-4-phenyl-3-butenoic acid dissolved into 115 ml of CHCl₃.

The mixture is stirred 2 hours at +20° C, 200 ml CHCl₃ are added (to provide a complete solution), and the resulting mixture is poured into 1 liter of iced water.

The chloroform is separated, washed with 150 ml of 10% aqueous HCl with 150 ml, of 10% aqueous NaHCO₃ and with water to neutrality.

After drying over sodium sulphate and evaporating under vacuum, there is obtained 150 g. of diethanolamide (IIIc) having ζ_(max) ^(MeOH) 245 mμ (E₁ cm^(1%) 620 ), I.R. nujol bands at 3400, 3280, 1620, 1320, 1300, 1260, 1210, 1170, 1090, 1070, 1020, 950, 910, 880, 870, 860, 840, 810, 770, 750, 700 cm⁻¹.

Diethylamide of 3-methyl-4-phenyl-3-butenoic acid (IIId).

1.93 liters of diethylamine dissolved into 5.1 liters of CHCl₃ are treated at -10° C during 1 hour with 1.65 kg of chloride of 3-methyl-4-phenyl-3-butenoic acid dissolved into 2.25 liters of CHCl₃.

The mixture is then stirred while allowing the temperature to rise to 20° C, it is poured into 25 liters of water, separated.

The chloroformic phase is washed with 8 liters 10% aqueous HCl, with 2 × 8 liters of water, with 8 liters of 10% aqueous NaOH, and with water to neutrality.

After drying over sodium sulphate, evaporating, diethylamide (IIId) is distilled at 0,5 mm, 134° - 136° C, and it is obtained kg 1,4 of product with ζ_(max) ^(MeOH) 245 mμ(E₁ cm^(1%) 631), I.R. thin layer bands at 2980, 2970, 1640, 1470, 1430, 1380, 1360, 1320, 1260, 1220, 1140, 1100, 1070, 1030, 790, 740, 700 cm⁻¹.

Morpholide of 3-methyl-4-phenyl-3-butenoic acid (IIIe).

191,5 g of morpholine (2,2 moles) dissolved into 700 ml of CHCl₃ are treated at -20° C during 1 hour with the solution made from 194,5 g of chloride of 3-methyl-4-phenyl-3-butenoic acid in 250 ml of CHCl₃.

The temperature is allowed to rise to 20° C within 1 hour, the mixture is poured into 3 liters of water, is separated.

The chloroformic phase is washed with 1 liter 10% aqueous HCl, with 10% aqueous NaHCO₃, with water to neutral.

After drying over sodium sulphate, evaporating, the residue is taken up with ethyl ether.

Upon standing 4 days, big crystals of the product separate, is filtered, and washed with ether 78 g morpholide (IIIe) are obtained, with m.p. 49°-51° C, ζ_(max) ^(MeOH) 245 mμ (E_(1cm) ^(1%) 620), carbon 73.80% (calculated 73.43%), hydrogen 7.46% (calculated 7.80%), nitrogen 5.86% (calculated 5.71%). 

We claim:
 1. A method of treating hypolipemia in a hypolipemic patient which comprises administering to said patient an effective amount of the diethylamide of 3-methyl-4-phenyl-3-butenoic acid.
 2. Diethylamide of 3-methyl-4-phenyl-3-butenoic acid. 